Autoimmune disorders (ADs) represent a major burden to the health care system and are a significant public health concern; as high as 10% of the population is affected by one or more ADs. The overall goal of this proposal is to investigate the role of maternal-child (fetal) genetics using several analytical approaches in two common ADs: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Female predominance, onset during childbearing years, and immunologic similarities to graft-versus-host disease (GVHD) support the hypothesis that natural processes during pregnancy, such as the bi-directional cellular exchange between mother and child (fetus) contribute to autoimmune disease etiology. The presence in one individual, of cells or tissues originating from another individual, is known as microchimerism (MC). Fetal cells have been shown through both human and animal studies to persist for decades in mothers. Overall, the exact role of MC remains unknown and may be protective or contribute to disease susceptibility. Maternal-child (fetal) genetics are important in this regard. Human Leukocyte Antigen (HLA) molecules are involved in immunologic function and are important in immune recognition of self and non-self. Histocompatibility is therefore likely to play a role in both effect and persistence of fetal cellsin the mother. HLA and other established autoimmune variants may influence RA and SLE through non-inherited effects. We will utilize samples, resources and data available through the UCSF Mother-Child Immunogenetic Study in Autoimmunity (MCIS) and the Inova Translational Medicine Institute (ITMI) to pursue three independent, but complementary Study Aims. We propose the use of 4-digit HLA genotypes and whole genome data, detailed pregnancy histories, clinical and environmental exposure data collected for 900 RA cases, SLE cases and healthy controls (300 females in each group), 1,500 of their children and 400 fathers, 900 mothers of cases, 5,000 unrelated males, and 1,500 additional control trio families (4,500 individuals) to fully address our study hypotheses. At least 13,000 individuals will be studied. We will investigate: 1) the association between both maternal-child HLA (major) and minor histocompatibility and susceptibility to RA and SLE in mothers; 2) the association between maternal-child histocompatibility influences and time to disease onset and specific clinical outcomes in mothers with RA and SLE; and 3) associations between non-inherited genetic and non-random mating effects in RA and SLE. Maternal-child (fetal) influences on risk of AD mediated through classical HLA and other immunogenotypes will provide new insight into the etiology of these debilitating conditions and others where factors related to pregnancy are suspected.]